Enhanced pre-ovulatory progesterone levels in fertile cycles during clomiphene citrate treatment

We compared ovulatory changes in fertile and preceding infertile cycles in 21 patients with unexplained infertility conceiving after clomiphene citrate treatment. No significant differences were observed in follicular growth, cervical score and follicle stimulating hormone (FSH) levels. Progesterone was higher (P less than 0.05) in the 2 days preceding ovulation in fertile cycles, luteinizing hormone (LH) higher (P less than 0.05) the day before, and 17-beta-estradiol lower (P less than 0.05) 4 days before. Stimulating progesterone secretion by systematic LH administration before ovulation could improve secretory endometrial transformation and thus reproductive prognosis.     

Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome

Purpose

The aim was to test a new protocol of luteal phase administration of clomiphene citrate (CC) for ovulation induction in women with polycystic ovary syndrome (PCOS).

Methods

This was a prospective, randomized, controlled trial. Two hundred and fifty-two women (cycles) with PCOS were utilized to create two groups. Patients in Group 1 (126 patients) received 100 mg of CC daily for 5 days starting on day 5 of menses, and patients in Group 2 (126 patients) received 100 mg of CC daily for 5 days starting the next day after finishing medroxyprogesterone acetate (MPA) (before withdrawal bleeding). The main outcome measures were the number of growing and mature follicles, serum E2 (in pg/mL), serum progesterone (in ng/mL) levels, endometrial thickness (in mm), pregnancy, and miscarriage rates.

Results

The total number of follicles and the number of follicles ≥14 mm during stimulation were significantly greater in Group 2. The endometrial thickness at the time of human chorionic gonadotrophin (hCG) administration was significantly greater in Group 2 as compared to Group 1 (7.84 ± 1.22 and 8.81 ± 0.9, respectively). Serum E2 levels were also significantly higher (p < 0.05) in Group 2 as compared to Group 1 (449.61 ± 243.45 vs. 666.09 ± 153.41 pg/mL). Pregnancy occurred in 13 patients (10.3 %) in Group 2 and in 11 patients (8.7 %) in Group 1. The difference was not statistically significant.

Conclusion

Luteal phase administration of CC in patients with PCOS leads to increased follicular growth and endometrial thickness, which might result in a higher pregnancy rate.     

The primary treatment of luteal phase inadequacy: progesterone versus clomiphene citrate

This study was undertaken in order to evaluate the superiority, if any, of progesterone or clomiphene citrate in treatment of infertile women with luteal phase inadequacy. Eighty-two patients were randomly treated with progesterone or clomiphene citrate. Some patients with failure of progesterone were changed to clomiphene citrate treatment; some patients with failure of clomiphene citrate were changed to progesterone treatment. A life-table analysis was used for evaluation of the results. No statistical difference was noticed between the two treatments. Seventeen of 57 patients treated with progesterone and 13 of 62 patients treated with clomiphene citrate conceived. It is recommended that: patients with luteal phase inadequacy can be treated primarily with progesterone; an endometrial biopsy should be performed if the patients fail to conceive; if endometrial biopsy continues to be abnormal the patients can be treated again with clomiphene citrate. Some alternative treatments for luteal phase inadequacy are needed.     

Luteal phase serum estradiol and progesterone in in vitro fertilization

One hundred seventy-five cycles in patients with irreparable tubal disease were stimulated by human menopausal gonadotropin/human chorionic gonadotropin for the purpose of in vitro fertilization. The pregnancy rate was found to be related to the height and pattern of serum estradiol (E2) response in the follicular phase. The mean serum E2 and progesterone (P) during the luteal phase showed no statistically significant difference between the pregnant and nonpregnant patients in the series except after luteal day 11. The mean serum E2 in most of the luteal phase days was highest in the high responders followed by the normal and the low responders. However, the mean P values were similar for the high and normal responders but higher than the low responders on cycle days 18, 20, and 22. The mean serum E2 and P in the luteal phase showed no statistically significant difference among the three most common patterns. This was also true for the pregnant and nonpregnant values in each category of height and pattern of response. We concluded that the success and failure of in vitro fertilization was probably less related to the peripheral E2 and P in the luteal phase than to the number and quality of eggs.     

Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome: a systematic review and meta-analysis

Objective: To assess the efficacy of late luteal phase clomiphene citrate (CC) administration relative to early follicular phase CC for ovulation induction for polycystic ovary syndrome (PCOS).

Study design: Review.

Materials and methods: A complete electronic databases including PubMed, Embase, The Cochrane Library, Web of Science, and CBM were searched for relevant randomized controlled trials (RCTs). The search was not restricted by language and publication time. Two reviewers selected trials and assessed trial quality by the Cochrane Handbook 5.1.0 independently.

Results: Four eligible RCT studies involving 708 women (934 cycles) were included. The results of the Meta-analysis: Late luteal phase group was associated with a number of higher total follicles (MD 1.82; 95% CI 0.86–2.78, p?p?p?=?0.26), ovulation rate (RR 0.99; 95% CI 0.86–1.14, p?=?0.87), and abortion rate (RR 1.12; 95% CI 0.38 to 3.29, p?=?0.84) between the two groups.

Conclusion: It appeared that late luteal phase CC for ovulation induction might be an effective method for ovulation induction in women with PCOS compared to conventional CC administration. Further intensive randomized-controlled studies should be warranted to define the efficacy of CC used in late luteal phase.     

Transaminitis after treatment with clomiphene citrate: a case report

BACKGROUND: Clomiphene citrate is widely used to induce ovulation in infertile women with anovulation. The manufacturer reports transaminitis as a possible side effect, but no case reports were found on a literature search. CASE: A 30-year-old, Somali woman, gravida 3, para 1021, was referred for evaluation after trying unsuccessfully to conceive for 19 months. She was diagnosed with unexplained infertility and prescribed clomiphene citrate for ovulation induction. The patient took the medication in 2 consecutive cycles and each time developed intense right upper quadrant pain. During the second episode she presented to the emergency room with transaminitis. Acute and chronic viral hepatitis were ruled out, and she had not ingested any other medications; ultimately, no other etiology was discovered. The transaminitis resolved over 2 months and, in the absence of further treatment with clomiphene citrate, did not recur. CONCLUSION: Transaminitis is a rare complication of treatment with clomiphene citrate. Liver function testing is warranted in patients with new-onset right upper quadrant pain after starting treatment with clomiphene citrate.     

Oral clomiphene citrate and vaginal progesterone suppositories in the treatment of luteal phase dysfunction: a comparative study

Oral clomiphene citrate (CC) and vaginal progesterone suppositories (PS) are common treatment modalities in luteal phase dysfunction (LPD). Little is known regarding the relative efficacy of these agents. To study the use of CC and PS in the management of LPD, a retrospective cohort study of patients presenting with infertility was undertaken. Sixty-five patients in whom LPD was diagnosed and corrected, as judged by endometrial biopsies, were studied; 35 were treated with PS and 30 with CC. Using Student's t-tests and chi-square analyses, the two treatment groups were demographically comparable. Using life-table analysis, no one therapeutic approach proved superior. Clomiphene citrate and PS are comparable treatment modalities in the setting of LPD given correction of endometrial lag.     

Induction of luteal phase defect with clomiphene citrate

The effect of clomiphene citrate and progesterone on luteal function in infertile women was studied. Endometrial biopsies were performed in 103 women immediately prior to menstruation. Group 1 (n = 62) had secretory endometrium with a histologic lag time of ≥48 hours with respect to the subsequent menses, that is, luteal phase defect. Group 2 (n = 10) had normal histologic characteristics of the secretory phase. Group 3 (n = 31) had anovulatory endometrium. The last group was subdivided into those with polycystic ovary syndrome (n = 9) and those without the characteristic gonadotropin pattern of polycystic ovary syndrome (n = 22). Clomiphene citrate at doses of 50 to 250 mg daily for 5 days was administered for induction of ovulation, timing of ovulation, or treatment of luteal phase defect. An endometrial biopsy was obtained after three ovulatory treatment cycles. Only one fourth of the women with prior luteal phase defect had normalization of the biopsy specimen with clomiphene citrate, while one half of those treated with progesterone had normal specimens. Half of the normally ovulating women had induction of a luteal phase defect with clomiphene citrate. Only women with polycystic ovary syndrome had consistently well-timed endometrial histologic features with clomiphene citrate therapy. Despite successful induction of ovulation, 16 of the other 22 previously anovulatory women had endometrial histologic findings compatible with luteal phase defect. Increasing the clomiphene citrate dosage was unsuccessful in improving endometrial maturation. These results suggest that the use of clomiphene citrate may be associated with a high rate of luteal phase defect induction, except among women with polycystic ovary syndrome. Clomiphene citrate, even at high doses, appears to be ineffective therapy for luteal phase defect.     

Effect of clomiphene citrate on ovulation after treatment withdrawal

The effect of clomiphene citrate (CC) on ovarian function in cycles subsequent to treatment withdrawal was studied. Thirty two out of 45 patients with anovulation due to polycystic ovarian syndrome (PCOS) and with no other factor affecting fertility who got pregnant were included. All patients received CC to induce ovulation. Pregnancies in CC treated cycles and after treatment were recorded. Twenty pregnancies were achieved during CC treated cycles and 12 in the cycles after it was withdrawn. In the latter group, eight pregnancies were achieved in the cycle following CC therapy, and four in the second subsequent cycle. In relation to pregnancy complications no significant statistical differences were found between the group of patients who became pregnant during the stimulation cycles and in the cycles after CC. Received: December 1996 / Accepted: April 1997     

Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women

A direct adverse effect of clomiphene citrate on the endometrium has been presumed, and interference with estrogen receptor-mediated endometrial estrogen receptor and progesterone receptor induction has been implicated as the mechanism responsible for an increased incidence of luteal phase deficiency in association with clomiphene citrate treatment. To clarify the net influence of clomiphene administration on endometrial steroid receptor induction, we studied five normal ovulatory women, in both a spontaneous and clomiphene-induced (150 mg/day, cycle days 5 to 9) ovulatory cycle. From cycle day 11 blood samples were obtained daily and urinary luteinizing hormone determinations were performed twice daily. Endometrial biopsy was performed on the day of the urinary luteinizing hormone surge and again 13 days after the surge. Serum levels of follicle-stimulating hormone and luteinizing hormone were determined by immunoradiometric assay, estradiol and progesterone by radioimmunoassay, and clomiphene citrate isomer concentrations in treatment cycles by reversed-phase high-performance liquid chromatography and fluorescence detection. Total, cytosolic, and salt-extracted nuclear endometrial estrogen receptor and progesterone receptor concentrations were determined by enzyme-linked immunoassay. Serum estradiol was threefold to fivefold higher (p less than 0.05) in clomiphene-induced than in spontaneous cycles 8 and 10 days before the luteinizing hormone surge, and progesterone was increased (p less than 0.05) from the day of the surge to end of the cycle. Serum enclomiphene rose to plateau between 12 and 6 days before the luteinizing hormone surge (4.1 +/- 0.8 ng/ml, mean +/- SE, n = 19) and fell thereafter to less than 1.0 ng/ml. Zuclomiphene levels increased rapidly between 14 and 8 days before the surge (53.9 +/- 2.8 ng/ml, mean +/- SE, n = 5) and then decreased gradually but remained elevated throughout the luteal phase (29.0 +/- 1.2 ng/ml, mean +/- SE, n = 33). Late luteal endometrial histology was abnormal in one of four available treatment cycle specimens, but the endocrine characteristics and number and subcellular distribution of estrogen receptor and progesterone receptor in the abnormal cycle were not different from those of normal, in-phase cycles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of ovulation by combined clomiphene citrate and dexamethasone treatment in clomiphene citrate nonresponders

Fifteen anovulatory, oligomenorrheic, hyperandrogenic and normoprolactinemic women who failed to respond to prolonged clomiphene citrate (CC) treatment, were subsequently treated with CC and small doses of dexamethasone (Dex). Twelve (80%) of the patients ovulated according to BBT and progesterone values, and 7 (49%) conceived during 3–6 treatment cycles. Five of these pregnancies terminated in live, single, full term deliveries, one set of twins and one first trimester abortion.It is concluded that a regimen of combined CC and a small dose of Dex may be offered to CC nonresponders as an effective alternative to Menotropins—HCG treatment.     

Correction of the luteal phase defect with clomiphene citrate.

Among the various strategies proposed for the therapy of the luteal phase defects (L.P.D.), the administration of clomiphene citrate during the early follicular phase has proved to be very effective even though it is not one of the most used. Nevertheless, very soon has been risen the question if such drug acts by an overphysiological increase of the hormonal levels or instead by a re-balance of the altered latter ones. In order to answer this question a clinical study was carried out during 265 cycles on 63 normally ovulating and menstruating women, whose 27 with a luteal phase defect (L.P.D.), detected by clinical, echographic, endocrine, and morphological criteria. Each of these latter patients were given clomiphene citrate, 100 mg per day from the 2nd to the 6th day of the cycle, for a total of 108 cycles. The other 36 women without any luteal abnormality, were used during 156 cycles, as a control group. At the end of our study there were no significant differences in all parameters between two studied groups. This suggest that early follicular phase administration of clomiphene citrate in these pathologies can act by gradually improving the luteal function.     

Luteal phase dysfunction in endometriosis: elevated progesterone levels in peripheral and ovarian veins during the follicular phase

Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.     

克罗米芬联合促卵泡素治疗多囊卵巢综合征的疗效观察

目的:比较单用克罗米芬(CC)及其联合不同促卵泡素(FSH)治疗多囊卵巢综合征(PCOS)患者的效果,以指导PCOS患者选择合适的促排卵方案.方法:选取2009年1月至2012年7月就诊于我院生殖门诊的81例PCOS患者(共92周期),患者均以CC促排卵,根据月经第8天的卵泡生长情况,决定是否联合应用基因重组促卵泡素(rFSH)或尿促卵泡素(uFSH).按促排卵方案不同将患者分为3组:CC+ HCG组(A组,26例,32周期);CC+rFSH+HMG+HCG组(B组,23例,26周期);CC+uFSH+HMG+HCG组(C组,32例,34周期).患者排卵后均用黄体酮胶丸或地屈孕酮黄体支持12 ～ 14天.比较3组患者促排卵治疗的效果.结果:A组中2例患者发生黄素化综合征(LUFS);B组中4例发生轻度卵巢过度刺激综合征(OHSS);C组中1例发生重度OHSS,1例LUFS.3组患者的HCG日最大卵泡直径、内膜厚度、排卵率及妊娠率均无显著差异(P＞0.05).A组D8优势卵泡直径大于B、C组(P＜0.05);至HCG日平均时间少于B、C组(P＜0.05);B组直径≥1.5cm卵泡数和排卵数均显著高于A、C组(P＜0.05).B组与C组的至HCG注射日时间和FSH用量均无显著差异(P＞0.05).结论:CC促排周期D8优势卵泡直径大小对决定联合FSH治疗PCOS患者有一定的参考意义.单用CC促排卵可能抵抗周期,联合uFSH是经济有效的促排卵方案.     

Simultaneous intrauterine and ovarian pregnancy following treatment with clomiphene citrate

Heterotopic pregnancy is increasingly being diagnosed since the advent of assisted reproductive technology involving the use of superovulatory drugs and/or in-vitro fertilization and the availability of high-resolution ultrasound scans. There are reports of Heterotopic tubal pregnancies following clomiphene use. Heterotopic ovarian pregnancies are however rare. Clomiphene citrate, which is widely used in the primary care setting to treat anovulatory infertility, is felt safe. We present a case of heterotopic ovarian pregnancy following treatment with clomiphene citrate. The diagnosis and management of heterotopic ovarian pregnancy are also discussed.